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Q&A With Dr. Gabriel N. Hortobagyi

BCRF sat down with Dr. Gabriel N. Hortobagyi to discuss his current work and interest in breast cancer research. Read on to learn more.

 

Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?

A: Since my childhood, my mother fed me books which fueled my interest in reading, especially about science, so I always knew I was going to be a doctor. I was very pleased that I could reach where I had set out to go.

When I started my residency in Internal Medicine at Case Western Reserve University Hospital System in Cleveland, Ohio, my boss, an endocrinologist, was a translational investigator, although at that time the word or term didn't exist. Working with him in the lab added to my existing interest in research. But it was really the clinical part of oncology that got me into the field. I saw a few patients, who were young and had metastatic breast cancer, and they had a huge impact on me.

In the early '70s, oncology was largely in the hands of radiologists and surgeons. There was no real consideration of a role for medical oncologists. The tools just were not there. The first modern oncology drugs were just starting to come onboard. Adriamycin (a.k.a. doxorubicin) was still an experimental drug, and tamoxifen was not even on this side of the ocean yet. Overall, the rest of the medical profession looked at cancer as this terribly hopeless and depressing field where nothing could be accomplished. It was a very different world. However, there were a few pioneers who were fascinated and passionate about the treatment of cancer, who obviously had to be hopelessly optimistic, otherwise they couldn't have survived and prospered.

During my residency, Professor Emil J. Freireich, who at that time was already at MD Anderson Cancer Center, gave a stellar lecture in Columbus. I drove down from Cleveland just to hear him. It was the first time I had heard someone coming up with statements, such as "Acute leukemia can be cured. We will do something similar to other cancers if we're given the tools, the resources, and the possibilities." Hearing "We're never going to give up hope. We are going to move forward, and yes we are going to do it!" was such a breath of fresh air. I then applied to several places for training, but I really just wanted to train with Dr. Freireich. I was accepted and came down to MD Anderson where I've been ever since.

Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?

A: Dr. Mien-Chie Hung has been my co-conspirator in research, both within the context of BCRF and outside of it, for about 20 years. He is an outstanding laboratory scientist who trained with Robert (Bob) Weinberg, PhD at the Whitehead Institute at MIT, so he came with a very high level of scientific rigor and accomplishment.

Cancer is a complex disease, and the first crucial step towards modern oncology care was to understand that cancer was a disease of genes and gene abnormalities. Every cancer is the result of one, or more, gene abnormalities of some sort. For instance, nucleic acids, which are the basic building blocks of our DNA, can be exchanged, and gene segments might be removed, deleted, or translocated onto other chromosomes. As a result, among the most significant of our studies is our work on gene therapy.

Dr. Hung and I have focused on identifying gene abnormalities that are commonly found in cancer or can be targeted by specific drugs. We concentrated on a built-in program in all of our cells called "apoptosis," which is an innate mechanism that induces cells to self-destruct. Apoptosis is an important part of our normal development and health maintenance. For example, cells that are important in making us grow and develop during childhood and adolescence eventually lose their function and need to disappear, so they die. Also, throughout life, by apoptosis, our bodies get rid of cells that experience irreversible damage whether caused by exposure to radiation or chemicals. Apoptosis is a mechanism that is either lost or the function of which is decreased in some cancers. Dr. Hung and I hypothesized that if we could enhance the process of apoptosis within cancer cells, then we could induce cancer cells to die while allowing normal cells to continue to live and reproduce happily ever after. But how can we make cancer cells self-destruct?

First, we identified a gene called Bik and were able to mutate it to enhance its apoptosis capability. (We called the mutated version BikDD.) Then, the challenge became how do we replicate that in a living cancer cell? So, we worked with viruses and retro-viruses, because in the lab, you can load viruses with mutated genes, which will go into cancer cells and cause them to self-destruct. However, the problem is that our bodies are too smart. They eventually develop immunologic reactions to these viruses. You can trick the body successfully only a few times. After that, the antibodies that our bodies produce will naturally destroy the viruses before the mutated genes can be activated and trigger apoptosis in cancer cells.

We then focused on little fat globules called liposomes. Fat globules are wonderful because they do not generate any immune reaction causing the body to immediately reject the mutated BikDD genes. You can load some molecular zip codes on liposomes, so they go exactly where you want them to go. Then, you can load them with the mutated BikDD gene cargo causing cancer cells to die. We were fortunate enough to get BCRF funding to develop this and went on to perfect it, which eventually led to the first clinical trial of its kind. We showed that we were actually able to safely deliver the cargo to cancer cells, and that the appropriate gene expressed itself resulting in some loss of cancer cells. And then we started to look at not only breast cancer but other cancers, and some moderately successful clinical trials have been completed.

Thanks to BCRF's support, we were able to attract additional outside funding for the BikDD studies. In 2012-2013, we plan to apply our BCRF grant towards a related project on triple negative breast cancer. This disease subtype is aggressive and occurs frequently in younger women. Currently, there is no targeted drug for it, making it hard to treat. We observed in triple negative cells many characteristics similar to tumor initiating cells (TICs, or cancer stem cells), for example their ability to spread or metastasize. The first priority of our analysis will be to focus on cancer-related kinases, which are enzymes that modify other proteins, to determine whether these kinases contribute to the cancer stem cell-like properties and metastatic abilities of triple negative breast cancer. Our preliminary results have given us a few clues, and we plan to follow up on these. This research can potentially identify new therapeutic targets for triple negative breast cancer and allow for the development of new treatments.

Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?

A: Breast cancer, which we used to think of as a single disease, is clearly a conglomerate of multiple genetically defined, or molecularly defined, diseases that require different treatments and that have different behaviors. So increasingly, as we become more sophisticated in identifying the subsets by different molecular techniques, we will identify an increasing number of smaller and smaller subsets but better characterized subsets of breast cancer, and within each subset we will identify specific molecular targets.

This presents huge challenges for the pharmaceutical industry and for us as physicians and researchers, because we will multiply from the 200 or so cancers that we recognize today. It will be 5,000 or even 10,000 different cancers - just imagine keeping those in mind. But I think that's where we're heading. In breast cancer, we already have distinct treatment regimens for the four major subtypes we accept today. That trend will proliferate beyond breast cancer. We will need increasingly smart scientists to identify these subsets, to identify the molecular targets, and to simultaneously develop markers and specific targeted therapies for them.

Q: What other projects are you currently working on?

A: Another of our research interests is angiogenesis, which is the process by which new tissue, especially new cancer tissue, grows or attracts blood vessels. Once a cancer cell gets loose from the original tumor and travels to another organ, it can divide and reproduce a few times but once it reaches the size of about 1 cubic millimeter, unless it can find some source of food and oxygen, which are provided by blood vessels, it cannot survive and will die.

However, cancer cells can develop substances that attract blood vessels assuring themselves access to nutrients and oxygen. Avastin® (bevacizumab) is one drug that was developed to interfere with cancer cells' ability to attract new blood vessels. So, we decided to refine the concept. Since angiogenesis is a normal and natural process, we don't want it to stop everywhere. We just want it to stop in the tumor. And maybe we can strengthen the anti-tumor effects of anti-angiogenesis by combining it with a drug. Then, we can use the anti-angiogenic substance to essentially drive the other anti-tumor agent to the cancer cells and nowhere else but to the cancer cells. And that developed into a very exciting project in which we administer a fusion protein. The combination of a drug called endostatin, which targets preferentially the blood vessel cells of cancers, with a cytotoxic drug (a drug that kills cells) enters the blood vessels of cancer cells. Once inside the cancer cells, the two drugs are separated and released like a bull in a china shop thereby destroying the cancer cells. We are preparing to initiate a clinical trial with that fusion protein.

Also, as a side observation of the liposomal BikDD project, we came to the field of cancer stem cells. This work has also benefited from BCRF support. The great majority of cells inside a tumor will grow for a while, and then they will die. They have no ability to create new tumors. But there is a very small minority of cells within that cancer called tumor initiating cells, or cancer stem cells, which have an infinite ability to create and generate new cells, including new cancer stem cells. These stem cells appear to be largely resistant to most of the treatments we have available today. However, we noticed that the BikDD gene is not only effective against cancer cells in general but also particularly effective against these cancer stem cells. We have had several successes on this front that culminated in an important publication last September in the journal Cancer Cell. We will continue this investigation in addition to others in our lab.

Q: How close are we to preventing and curing all forms of breast cancer?

A: Breast cancer is the prototype for cancer prevention. Today, we can prevent about 60% of those breast cancers that carry the estrogen receptor, which represent about 70% of all breast cancers, so 60% of 70% would be about 40% of all breast cancers. We have demonstrated through large clinical trials that we can prevent that number or that proportion by using drugs such as tamoxifen, raloxifene, or an aromatase inhibitor. Unfortunately, the uptake in the medical community and the patient community has not been very good - fewer than 4% of those women who would be eligible by the results of those clinical trials have actually considered or initiated this cancer prevention strategy. So, we need to figure out why and how to improve the acceptance of this preventive intervention and perhaps develop approaches that might be more acceptable to people. But we already have a very, very powerful set of tools--just imagine, we have the ability today to eliminate 40% of breast cancers before they occur.

Q: In your opinion, how has BCRF impacted breast cancer research?

A: BCRF support enabled Dr. Hung and me to develop these high-risk concepts rapidly and without the bureaucratic hassles common with other sources of funding. With BCRF support we were able to develop three novel therapeutic concepts, generate the necessary preclinical data and leverage BCRF investment into greater level of support from the National Institutes of Health. None of this would have been possible without the support of BCRF. BCRF has been enormously generous and supportive of our efforts.

As we discussed earlier, BCRF's research dollars have greatly advanced our understanding of the roles played by gene therapy, angiogenesis, and cancer stem cells in breast cancer causation and treatment, and its support of clinical trials has changed the landscape of breast cancer research.

 

Read more about Dr. Hortobagyi's current research project funded by BCRF.